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Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages

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  • Jin Jin

    (The University of Texas MD Anderson Cancer Center)

  • Yichuan Xiao

    (The University of Texas MD Anderson Cancer Center)

  • Hongbo Hu

    (The University of Texas MD Anderson Cancer Center)

  • Qiang Zou

    (The University of Texas MD Anderson Cancer Center)

  • Yanchuan Li

    (The University of Texas MD Anderson Cancer Center)

  • Yanpan Gao

    (National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences)

  • Wei Ge

    (National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences)

  • Xuhong Cheng

    (The University of Texas MD Anderson Cancer Center)

  • Shao-Cong Sun

    (The University of Texas MD Anderson Cancer Center
    Center for Inflammation and Cancer, The University of Texas MD Anderson Cancer Center
    The University of Texas Graduate School of Biomedical Sciences at Houston)

Abstract

Signal transduction from toll-like receptors (TLRs) is important for innate immunity against infections, but deregulated TLR signalling contributes to inflammatory disorders. Here we show that myeloid cell-specific ablation of TRAF2 greatly promotes TLR-stimulated proinflammatory cytokine expression in macrophages and exacerbates colitis in an animal model of inflammatory bowel disease. TRAF2 deficiency does not enhance upstream signalling events, but it causes accumulation of two transcription factors, c-Rel and IRF5, known to mediate proinflammatory cytokine induction. Interestingly, TRAF2 controls the fate of c-Rel and IRF5 via a proteasome-dependent mechanism that also requires TRAF3 and the E3 ubiquitin ligase cIAP. We further show that TRAF2 also regulates inflammatory cytokine production in tumour-associated macrophages and facilitates tumour growth. These findings demonstrate an unexpected anti-inflammatory function of TRAF2 and suggest a proteasome-dependent mechanism that limits the proinflammatory TLR signalling.

Suggested Citation

  • Jin Jin & Yichuan Xiao & Hongbo Hu & Qiang Zou & Yanchuan Li & Yanpan Gao & Wei Ge & Xuhong Cheng & Shao-Cong Sun, 2015. "Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages," Nature Communications, Nature, vol. 6(1), pages 1-12, May.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms6930
    DOI: 10.1038/ncomms6930
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